Hypocholesterolemic agents have evolved rapidly when hypercholesterolemia is well recognized as a primary risk factor in atherosclerotic diseases and coronary heart diseases. A class of drugs, such as 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) inhibitors, the statins, are currently potent hypocholesterolemic agents. (Cai Z-Y, Zhou W—C. Progresses in researches of HMG CoA reductase inhibitors, Chinese Journal of New Drugs, 2006, 15 (22): 1907-1911). The launched drugs, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin are currently available hypocholesterolemic agents. However, as far as human requirement is concerned, there is a need to develop new potent hypocholesterolemic drugs.
The structure of the fully synthetic statins is characterized by desmethylmevalonic acid or the lactone, the pharmacophore which is connected to a lipophilic ring, such as hexahydronaphthalene, indole, pyrrole, pyrimidine, or quinoline. Systematical QSAR study on quinoline statin compounds, such as pitavastatin, show desmethylmevalonic acid linked through a trans-ethylene group to position 3 in quinoline exhibited good activity in inhibiting HMG CoA reductase. The introduction of chloro, methyl or methoxy etc. to the 6-, 7- or 8-position of the quinoline nucleus may increase the inhibitory potency. (Cai Z-Y, Zhou W-C. Progresses in researches of HMG CoA reductase inhibitors, Chinese Journal of New Drugs, 2006, 15 (22): 1907-1911). So far in the known quinolines as HMG CoA inhibitors, the aryl group such as 4-fluorophenyl, is directly linked to position 4 in quinoline, the derivatives from 4-thiohenyl have not been reported.